Pharmacophore modeling for the identification of small-molecule inhibitors of TACE

Pharmacophore modeling for the identification of small-molecule inhibitors of TACE

Tumor necrosis factor α-converting enzyme (TACE) plays a critical role in diverse physiological processes such as inflammation, hematopoiesis, and development. In this study, a pharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic c...

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Bibliographic Details
Main Authors: Liu, Li-Juan, Leung, Ka-Ho, Lin, Sheng, Chan, Daniel Shiu-Hin, Susanti, Dewi, Rao, Weidong, Chan, Philip Wai Hong, Ma, Dik-Lung, Leung, Chung-Hang
Other Authors: School of Physical and Mathematical Sciences
Format: Article
Language:English
Published: 2016
Subjects:
Pharmacophore
TACE
Online Access:https://hdl.handle.net/10356/82167
http://hdl.handle.net/10220/41148
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Institution: Nanyang Technological University
Language: English
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Summary:Tumor necrosis factor α-converting enzyme (TACE) plays a critical role in diverse physiological processes such as inflammation, hematopoiesis, and development. In this study, a pharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds, from which compound 1 emerged as a top candidate. In a cell-free assay, compound 1 inhibited TACE enzymatic activity in a dose-dependent manner. Moreover, compound 1 inhibited the production of soluble TNF-α in human acute monocytic leukemia THP-1 cells without impacting nitric oxide production, and exhibited anti-proliferative activity against THP-1 cells. We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors. This study also validates the use of pharmacophore modeling to identify enzyme inhibitors.

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